This invention is directed to the tetradecapeptides ##STR2## in which Y is L-Asn or L-Ala as well as to their pharmaceutically acceptable acid addition salts and to intermediates produced during the synthesis of the tetradecapeptides.
Somatostatin (also known as somatotropin release inhibiting factor) is a tetradecapeptide of the formula ##STR3## This tetradecapeptide was isolated from ovine hypothalamic extracts and was found to be active in inhibiting the secretion of growth hormone (GH), also known as somatotropin. In this regard, see P. Brazeau, W. Vale, R. Burgus, N. Ling, M. Butcher, J. Rivier, and R. Guillemin, Science, 179, 77 (1973).
The biologically active tetradecapeptides of this invention have the formula defined above and include the non-toxic acid addition salts thereof. Their structures differ from that of somatostatin by the presence of a D-serine residue in position 2 in place of a glycine residue, a D-tryptophan residue in position 8 in place of an L-tryptophan residue, and, optionally, an L-alanine residue in positon 5 in place of an L-asparagine residue. For convenience sake, the tetradecapeptides of this invention can be referred to as D-Ser.sup.2, D-Trp.sup.8 -somatostatin and D-Ser.sup.2, L-Ala.sup.5, D-Trp.sup.8 -somatostatin.
Thus, this invention is directed to a compound selected from those of the formula H-L-Ala-D-Ser-L-Cys-L- Lys-Y-L-Phe-L-Phe-D-Trp-L-Lys-L-Thr-L-Phe-L-Thr-L-Ser-L-Cys-OH and their pharmaceutically-acceptable non-toxic acid addition salts, and R-L-Ala-D-Ser(R.sub.4)-L-Cys(R.sub.1)-L-Lys-(R.sub.2 )-Y-L-Phe-L-Phe-D-Trp(R.sub.5)-L-Lys(R.sub.2)-L-Thr(R.sub.3)-L-Phe-L-Thr(R .sub.3)-L-Ser(R.sub.4)-L-Cys(R.sub.1)-X; in which
Y is L-Asn or L-Ala; PA1 R is hydrogen or an .alpha.-amino protecting group; PA1 R.sub.1 is hydrogen or a thio protecting group; PA1 R.sub.2 is hydrogen or an .epsilon.-amino protecting group; PA1 R.sub.3 and R.sub.4 each are hydrogen or a hydroxy protecting group; PA1 R.sub.5 is hydrogen or formyl; and PA1 X is hydroxy or ##STR4## IN WHICH THE RESIN IS POLYSTYRENE; WITH THE PROVISO THAT, WHEN X is hydroxy, each of R, R.sub.1, R.sub.2, R.sub.3, R.sub.4, and R.sub.5 is hydrogen, and, when x is ##STR5## each of R, R.sub.1, R.sub.2, R.sub.3, and R.sub.4 is other than hydrogen.